It is estimated that a quarter of Veterans being treated by the VA have diabetes, with numbers expected to rise in coming years, especially the incidence of Type-2 diabetes. Diabetic retinopathy is a significant cause of visual impairment in these patients and the leading cause of blindness for working age adults in the U.S. Diabetic retinopathy has long been considered a disorder of the retinal microvasculature, with most research to date focused on the retinal cells, themselves. However, recent paradigm-shifting studies have indicated that the inflammatory activity of immune cells, such as neutrophils and monocytes, are required to drive the early events in disease pathogenesis, yet little remains known about this critical process. This proposal is based on the hypothesis that that the innate immune system is dysregulated during diabetes and thus promotes a chronic inflammatory condition leading to direct retinal endothelial cell cytotoxicity and development of clinical retinopathy. To this end, targeted immunomodulation of the innate immune system will stem the inflammatory process and prevent retinal pathology. This will be tested in three specific aims using established pre-clinica models of both Type-1 and Type-2 diabetes. Specific Aim 1 will examine the intrinsic inflammatory pathways that are induced in neutrophils and monocytes to influence their systemic activity during diabetes. Specific Aim 2 will examine the extrinsic effector mechanisms used by neutrophils and monocytes to induce retinal inflammation. Specific Aim 3 will incorporate the knowledge gained from Aim 1 and Aim 2 to investigate and implement therapeutic strategies aimed at controlling myeloid cell inflammation and the chronic inflammatory process in order to prevent retinal inflammation and capillary degeneration characteristic of diabetic retinopathy. The candidate's long-term career goals are to establish a highly productive research program in the VA system defining the cellular and molecular immune processes that contribute to the major health problems facing Veterans. To this end, the candidate's immediate objectives are to 1) implement a career development and research plan focused on disease pathogenesis and innovative therapies to prevent diabetic retinopathy, 2) and to successfully transition to an independent investigator at the Louis Stokes Cleveland VAMC. With an established record of research success and accomplishments, the candidate has positioned himself for success during the CDA-2 award period and beyond as an established independent investigator in the VA system.